Add-on Reparixin in Adult Patients With ARDS

• ClinicalTrials.gov Identifier: NCT05496868
• Recruitment Status: Recruiting
• First Posted: August 11, 2022
• Last Update Posted: June 1, 2023
• Sponsor: Dompé Farmaceutici S.p.A
• Information provided by (Responsible Party): Dompé Farmaceutici S.p.A

Tracking Information

• First Submitted Date: August 4, 2022
• First Posted Date: August 11, 2022
• Last Update Posted Date: June 1, 2023
• Actual Study Start Date: February 7, 2023
• Estimated Primary Completion Date: May 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 9, 2022)

• Change in oxygenation index (OI) from baseline to day 7 of treatment [ Time Frame: to day 7 ]
  The OI is defined as: % mean airway pressure x FIO2/PaO2
• Ventilator free days (VFD) at day 28 [ Time Frame: at day 28 ]
  Number of days from successfully weaning to day 28; patients who died before weaning have no ventilator-free days

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 27, 2022)

• Change in oxigenation index (OI) from baseline to day 4 [ Time Frame: to day 4 ]
  The lower the OI the better the outcome
• Acute lung injury score [composite of PaO2/FIO2 ratio, PEEP, lung compliance (plateau airway pressure minus PEEP/TV) and extent of pulmonary infiltrates] at 2, 3, 7, 14 days (if still intubated) [ Time Frame: at 2, 3, 7, 14 days ]
• Sequential Organ Failure Assessment (SOFA) score at 2, 3, 7, 14 days (if still intubated) [ Time Frame: at 2, 3, 7, 14 days ]
• Ventilatory ratio (product of minute ventilation and PaCO2) at 2, 3, 7, 14 days (if still intubated) [ Time Frame: at 2, 3, 7, 14 days ]
• Incidence of Extracorporeal Membrane Oxygenation (ECMO) by day 14 [ Time Frame: by day 14 ]
• Use of vasoactive medications by day 14 [ Time Frame: by day 14 ]
• Chest X-Rays assessment of pulmonary edema by "radiographic assessment of lung edema" (RALE) score at 2, 3, 7, 14 days [ Time Frame: at 2, 3, 7, 14 days ]
• Percentage of patients achieving pressure support ventilation equal to 5 cmH20 with PEEP equal to 5 cmH20 for 2 hours (measure of weaning) by day 28 and at hospital discharge [ Time Frame: by day 28 ]
• Intensive Care Unit free days by day 28 and at hospital discharge [ Time Frame: by day 28 ]
• Hospital-free days by day 28 and at hospital discharge [ Time Frame: by day 28 ]
• Incidence of tracheostomies by day 28 and at hospital discharge [ Time Frame: by day 28 ]
• Incidence of transfer to long term acute care (LTAC) facility by day 28 and at hospital discharge [ Time Frame: by day 28 ]
• All-cause mortality by day 28 [ Time Frame: by day 28 ]
• All-cause mortality by day 60 [ Time Frame: by day 60 ]
• Change from baseline to day 3, 7 and 14 days in plasma levels of IL-6, IL-8, PAI-1, TNFr-1, ICAM-1 RAGE [ Time Frame: to day 3, 7 and 14 day ]
• Plasma levels (free and bound) of DF1681Y (acidic form of reparixin) and relevant metabolites (DF2188Y, DF2243Y, and ibuprofen (DF1674Y)) [ Time Frame: day 1, day 2, day 7, day 14 ]
  Plasma levels (free and bound) of DF1681Y (acidic form of reparixin) and relevant metabolites (DF2188Y, DF2243Y, and ibuprofen (DF1674Y)) are measured in a subset of about 24 (10-12 per group) patients selected at pre-defined sites.
• Incidence of Treatment Emergent AEs (TEAEs) and SAEs (TESAEs) from the beginning of study treatment to up to the end of study participation. [ Time Frame: from the date of First Patient First Visit (FPFV) to the date of Last Patient Last Visit (LPLV) ]
• eGFR, absolute value and change from screening to day 3(±8h), day 7±1, day 14±2, day 21±2 (if still receiving reparixin), day 28±2 [ Time Frame: to day 3(±8h), 7±1 day, 14±2 day, 21±2 day, 28±2 day ]
• Incidence of secondary infections defined as new by day 28±2 [ Time Frame: by day 28±2 ]
  Secondary infections defined as new (occurring after the first IMP intake) infection in a previously known to be sterile site, including blood, body fluid or tissue, or new pathogen isolated from cultures of biological samples known to be previously infected by day 28±2

Original Secondary Outcome Measures (submitted: August 9, 2022)

• Change in oxigenation index (OI) from baseline to day 4±1 [ Time Frame: to day 4±1 ]
  The lower the OI the better the outcome
• Acute lung injury score [composite of PaO2/FIO2 ratio, PEEP, lung compliance (plateau airway pressure minus PEEP/TV) and extent of pulmonary infiltrates] at 2(±8h) day, 3(±8h) day, 7±1 day, 14±2 day (if still intubated) [ Time Frame: at 2(±8h), 3(±8h), 7±1 day, 14±2 day ]
• Sequential Organ Failure Assessment (SOFA) score at 2(±8h) day, 3(±8h) day, 7±1 day, 14±2 day (if still intubated) [ Time Frame: at 2(±8h), 3(±8h), 7±1 day, 14±2 day ]
• Ventilatory ratio (product of minute ventilation and PaCO2) at 2(±8h) day, 3(±8h) day, 7±1 day, 14±2 day (if still intubated) [ Time Frame: at 2(±8h), 3(±8h), 7±1 day, 14±2 day ]
• Incidence of Extracorporeal Membrane Oxygenation (ECMO) by day 14±2 [ Time Frame: by day 14±2 ]
• Use of vasoactive medications by day 14±2 [ Time Frame: by day 14±2 ]
• Chest X-Rays assessment of pulmonary edema by "radiographic assessment of lung edema" (RALE) score at 2(±8h), 3(±8h), 7±1, 14±2 days [ Time Frame: at 2(±8h), 3(±8h), 7±1 day, 14±2 day ]
• Percentage of patients achieving pressure support ventilation equal to 5 cm H20 with PEEP equal to 5 cm H20 for 2 hours (measure of weaning) by day 28±2 [ Time Frame: by day 28±2 ]
• Intensive Care Unit free days by day 28±2 [ Time Frame: by day 28±2 ]
• Hospital-free days by day 28±2 [ Time Frame: by day 28±2 ]
• Incidence of tracheostomies by day 28±2 [ Time Frame: by day 28±2 ]
• Incidence of transfer to long term acute care (LTAC) facility by day 28±2 [ Time Frame: by day 28±2 ]
• All-cause mortality by day 28±2 [ Time Frame: by day 28±2 ]
• All-cause mortality by day 60 [ Time Frame: by day 60 ]
• Change from baseline to day 3(±8h), 7±1 day and 14±2 day in plasma levels of IL-6, IL-8, PAI-1, TNFr-1, ICAM-1 RAGE [ Time Frame: to day 3(±8h), 7±1 day, and 14±2 day ]
• Plasma levels (free and bound) of DF2156Y (acidic form of reparixin) and relevant metabolites (DF2108Y, S-isomer; DF2227Y, R-isomer) [ Time Frame: day 1, day 2, day 7, day 14 ]
  Plasma levels (free and bound) of DF2156Y (acidic form of reparixin) and relevant metabolites (DF2108Y, S-isomer; DF2227Y, R-isomer) are measured in a subset of about 24 (10-12 per group) patients selected at pre-defined sites.
• Incidence of Treatment Emergent AEs (TEAEs) and SAEs (TESAEs) from the beginning of study treatment to up to the end of study participation. [ Time Frame: from the date of First Patient First Visit (FPFV) to the date of Last Patient Last Visit (LPLV) ]
• eGFR, absolute value and change from screening to day 3(±8h), day 7±1, day 14±2, day 21±2 (if still receiving reparixin), day 28±2 [ Time Frame: to day 3(±8h), 7±1 day, 14±2 day, 21±2 day, 28±2 day ]
• Incidence of secondary infections defined as new by day 28±2 [ Time Frame: by day 28±2 ]
  Secondary infections defined as new (occurring after the first IMP intake) infection in a previously known to be sterile site, including blood, body fluid or tissue, or new pathogen isolated from cultures of biological samples known to be previously infected by day 28±2

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Add-on Reparixin in Adult Patients With ARDS
• Official Title: Phase 2, Randomized, Double-blinded, Placebo-controlled, Multicenter Study to Assess Efficacy and Safety of Reparixin as add-on Therapy to SoC in Acute Respiratory Distress Syndrome (RESPIRATIO)

Brief Summary

Study objectives

1. To characterize the efficacy of reparixin in ameliorating lung injury and systemic inflammation and expediting clinical recovery and liberation from mechanical ventilation in adult patients with moderate to severe ARDS (PaO2/FIO2 ratio ≤ 200).
2. To evaluate the safety of reparixin vs. placebo in patients enrolled in the study.

Detailed Description

Phase 2, randomized, double-blinded, placebo controlled, multicenter study. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care). Patients will be randomized (1:1) to either reparixin or placebo. Duration of treatment will be 14 days.

The study will consist of 4 study periods:

Screening Randomization and Baseline assessments, Treatment (14 days with discretionary extension up to 21 days), Follow-up (up to 28 days or hospital discharge, whichever occurs first, and then up to day-60).

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

the identity of the treatments will remain unknown to the subject, Investigator, site staff, CRO and Dompé's personnel until the study completion and formal unmasking. Only the Data Monitoring Committee (DMC) will have access to group-unblinded and/or fully unblinded DMC reports.

Primary Purpose: Treatment

• Condition: Acute Respiratory Distress Syndrome, Adult

Intervention

• Drug: Reparixin 600mg
  Reparixin will be administered through a nasogastric tube at the dose of 1200 mg (2 x 600 mg tablets) TID every 8 hours (6 tablets daily) for 14 days. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care).
  Other Name: REP
• Other: Matching Placebo
  Placebo will be administered through a nasogastric tube at the dose of 1200 mg (2 x 600 mg tablets) TID every 8 hours (6 tablets daily) for 14 days. All patients will receive therapy in line with current standard-of-care as it pertains to ARDS management (protocolized ventilator management will be made available to all sites in accordance with currently accepted standard of care).
  Other Name: Control

Study Arms

• Experimental: Reparixin + Standard of care
  Reparixin tablets 1200 mg TID (2 tablets x 600 mg TID) as add-on to the standard of care (SoC).
  Intervention: Drug: Reparixin 600mg
• Placebo Comparator: Placebo + Standard of care
  Placebo tablets with the same schedule of reparixin, as add-on to the standard of care (SoC)
  Intervention: Other: Matching Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 27, 2022): 66
• Original Estimated Enrollment (submitted: August 9, 2022): 73
• Estimated Study Completion Date: September 2023
• Estimated Primary Completion Date: May 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed Informed Consent, according to local guidelines and regulation.
2. Male and female adults (>18 years old).
3. Mechanically ventilated (invasive) patients with PaO2/FIO2 ratio ≤200 in the presence of PEEP of ≥5 cmH20.
4. Respiratory failure not fully explained by cardiac failure or fluid overload (if acute Congestive Heart Failure exacerbation is identified as part of the clinical picture this should be addressed effectively and as soon as possible before the patient can be enrolled).
5. Bilateral radiologic opacities consistent with pulmonary edema on the frontal chest x-ray (CXR), or bilateral ground glass opacities on a chest computerized tomography (CT) scan.
6. ≤48 hours from fulfilling above ARDS criteria.
7. ≤7 days from hospital admission.

8. Females of child-bearing potential who are sexually active must be willing not to get pregnant within 30 days after the last Investigational Medicinal Product (IMP) dose and must agree to at least one of the following reliable methods of contraception:

   1. Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives from at least 2 months before the screening visit until 30 days after the last IMP dose;
   2. A sterile sexual partner;
   3. Abstinence.

Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects with child-bearing potential, pregnancy test result must be negative before first drug intake.

Exclusion Criteria:

1. Moderate-severe chronic hepatic disease (as verified by relevant history, imaging, if pre-existent, and Child-Pugh score B-C).
2. Severe chronic renal dysfunction: eGFR (MDRD) < 30 mL/min/1.73m2 or End Stage Renal Disease on renal replacement therapy.
3. Participation in another interventional clinical trial.
4. Patients that are clinically determined to have a high likelihood of death within the next 24 hours based on PI's estimation.
5. Evidence of anoxic brain injury
6. Currently receiving ECMO or high frequency oscillatory ventilation.
7. Anticipated extubation within 24 hours of enrollment.
8. Active malignancy (with the exception of non-melanotic skin cancers).
9. Hemodynamic instability (>30% increase in vasopressor in the last 6 hours or norepinephrine > 0.5 mcg/Kg/min).
10. Evidence of gastrointestinal (GI) dysmotility e.g., due to acute pancreatitis or immediate post-op state, as demonstrated by persistent gastric distention, enteral feeding intolerability and/or persistent gastric residuals >500 ml).
11. Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening.
12. Decision to withhold or withdraw life-sustaining treatment (patients may still be eligible however if they are committed to full support except cardiopulmonary resuscitation if cardiac arrest occurs).

13. History of:

    1. Documented allergy/hypersensitivity to more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib (hypersensitivity to sulphanilamide antibiotics alone, e.g., sulfamethoxazole does not qualify for exclusion), and to the study product and/or its excipients.
    2. Lactase deficiency, galactosemia or glucose-galactose malabsorption.
    3. History of GI bleeding or perforation due to previous Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) therapy or recurrent peptic ulcer/haemorrhage.
    4. Hypersensitive to ibuprofen.
14. Active bleeding (excluding menses) or bleeding diathesis including patients on chronically high doses of NSAIDs.
15. Pregnant or lactating women.
16. Women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception during the study and up to 30 days after the last IMP dose.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Maria De Pizzol, BSc-PhD; +3902583831; clinops@pec.dompe.it

Contact: Cecilia Conz, M.Sc; +3902583831; clinops@pec.dompe.it

• Listed Location Countries: Germany, Italy, United States

Administrative Information

• NCT Number: NCT05496868
• Other Study ID Numbers: REP0122; 2022-001612-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dompé Farmaceutici S.p.A
• Original Responsible Party: Same as current
• Current Study Sponsor: Dompé Farmaceutici S.p.A
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Enrico Minnella, MD; Dompè farmaceutici SpA

• PRS Account: Dompé Farmaceutici S.p.A
• Verification Date: May 2023